# Mechanism of Vascular Impairment in Neurocognitive Disorders

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2021 · —

## Abstract

Vascular cognitive impairment and dementia (VCID) is the most common etiology of dementia in the elderly
including veterans. Since proportion of the elderly population is progressively increasing, VCID has become a
significant problem for elderly citizens, especially veterans. Therefore, the study of this disease is relevant to
veterans’ health and thus the mission of the Veterans Administration. VCID involves multiple risk factors, such
as hypertension, cardiac disease, obesity, and type 2 diabetes mellitus (T2DM). Over 40 million Americans
aged 70 years or older have at least one of these metabolic risk factors, yet we know relatively little about how
these risk factors contribute to VCID.
Recently, elevation of asymmetric dimethylarginine (ADMA) in blood has gained attention as a biomarker and
a risk factor for vascular disease. ADMA catabolism is reduced by decreased expression/activity of its catabolic
enzyme dimethylarginine dimethylaminohydrolase (DDAH) under conditions of vascular disease. Secondly,
DDAH dysfunction and ADMA elevation contribute to dysfunction of endothelial nitric oxide (NO) synthase
(eNOS) leading to vascular and endothelial disease. ADMA uncouples eNOS leading to dysfunction of redox-
based NO metabolism with excessive production of peroxynitrite (ONOOˉ). ADMA is also reported to reduce
cerebral blood flow (CBF) and blood-brain barrier (BBB) dysfunction. While decreased CBF and BBB disruption
have been highly implicated in the pathogenesis of VCID, the role of ADMA in VCID-related pathogenesis, as
well as underlying endothelial/vascular mechanisms are not well understood at present. Therefore, the goal of
proposed study is to investigate ADMA as an intermediary mechanism between the known risk factors and
VCID-related brain pathologies and to evaluate the therapeutic strategies targeting the ADMA-induced
endothelial eNOS/NO dysregulation for VCID associated brain disease.
To understand ADMA-mediated mechanisms in VCID, we have recently investigated the role of ADMA in
vascular and neurocognitive-pathologies in a mouse model of early-onset cerebral amyloid angiopathy (CAA:
Tg-SwDI). CAA is known to promote VCID through a number of mechanisms including inflammation,
hypoperfusion, and loss of BBB function and integrity. From these initial investigations, we discovered that
ADMA overburden during the course of CAA causes an increased BBB dysfunction, loss of brain microvessels,
neuroinflammation, and cognitive decline with increased endothelial nitrosative stress. These findings led us
to hypothesize that overburden of blood or brain ADMA levels, as a result of defective DDAH activity, drives
VCID-related microvascular pathogenesis in the brain by disturbing the vascular/endothelial NO homeostasis.
VCID is a multifactorial and complex disease. At present, therefore, there is no specific animal model that is
considered as the gold standard for assessing VCID pathology and therapeutics. We propose to investigate
the role of...

## Key facts

- **NIH application ID:** 10124681
- **Project number:** 1I01BX005190-01A1
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Avtar K Singh
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124681

## Citation

> US National Institutes of Health, RePORTER application 10124681, Mechanism of Vascular Impairment in Neurocognitive Disorders (1I01BX005190-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10124681. Licensed CC0.

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